NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Ina Schanze (1) , Jens Bunt (2) , Jonathan W.C. Lim (2) , Denny Schanze (1) , Ryan Dean (2) , Marielle Alders (3) , Patricia Blanchet (4, 5) , Tania Attié-Bitach (6) , Siren Berland (7) , Steven Boogert (1) , Sangamitra Boppudi (1) , Caitlin J. Bridges (1) , Megan T Cho (8) , William B. Dobyns (9, 10) , Dian Donnai (11) , Jessica Douglas (12) , Dawn Earl (10) , Timothy J. Edwards (2) , Laurence Faivre (13, 14, 15) , Brieana Fregeau (16) , David Geneviève (5, 4) , Marion Gérard (17, 18) , Vincent Gatinois (4, 5) , Muriel Holder-Espinasse (19) , Samuel F. Huth (2) , Kosuke Izumi (20) , Bronwyn Kerr (11) , Elodie Lacaze (21) , Phillis Lakeman (3) , Sonal Mahida (22) , Ghayda M. Mirzaa (10) , Sian M. Morgan (23) , Catherine Nowak (24) , Hilde Peeters (25) , Florence Petit (19) , Daniela T. Pilz (26) , Jacques Puechberty (4, 5) , Eyal Reinstein (27) , Jean-Baptiste Rivière (14, 13, 15) , Avni B. Santani (20) , Anouck Schneider (4, 5) , Elliott Sherr (16) , Constance Smith-Hicks (22) , Ilse Wieland (1) , Elaine Zackai (20, 28) , Xiaonan Zhao (20) , Richard Gronostajski , Martin Zenker (1) , Linda J. Richards (29)

1 OVGU - Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg]
2 Queensland Brain Institute
3 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
4 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
5 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
6 Equipe Inserm U1163 - Embryology and genetics of human malformation
7 Haukeland University Hospital
8 GeneDx [Gaithersburg, MD, USA]
9 University of Washington [Seattle]
10 Seattle Children’s Hospital
11 University of Manchester [Manchester]
12 Boston Children's Hospital
13 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
14 Equipe GAD (LNC - U1231)
15 FHU TRANSLAD (CHU de Dijon)
16 UC San Francisco - University of California [San Francisco]
17 Unité fonctionnelle de génétique clinique
18 Service de Génétique [CHU Caen]
19 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
20 CHOP - Children’s Hospital of Philadelphia
21 Département de génétique (groupe hospitalier le Havre)
22 Kennedy Krieger Institute [Baltimore]
23 UHW - University Hospital of Wales
24 Boston Children's Hospital
25 University Hospitals Leuven [Leuven]
26 University of Glasgow
27 Sackler Faculty of Medicine
28 Perelman School of Medicine
29 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.

Mots clés: haploinsufficiency; developmental delay; chromosome 9p23; intellectual disability; megalencephaly; macrocephaly; nuclear factor I; agenesis of the corpus callosum; chromosome 9p22.3; NFIB

Domaines: Génétique humaine

Ina Schanze, Jens Bunt, Jonathan W.C. Lim, Denny Schanze, Ryan Dean, et al.. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly. American Journal of Human Genetics, 2018, 103 (5), pp.752-768. ⟨10.1016/j.ajhg.2018.10.006⟩. ⟨hal-01999378⟩